Catalytic antibodies in hemophilia patients

This is the PhD project of my friend Bharath Wootla. It's interesting how his mentor Sébastien Lacroix-Desmazes guided by Srinivas Kaveri got this idea, and published in Nature Medicine, and a much bigger study later on in the New England Journal of Medicine. The idea is simple: congenital hemophilia patients lack the gene for factor VIII, a protein that is pivotal in blood coagulation pathway. When patients suffering from hemophilia undergo an injury, their blood does not clot and can lead to death due to bleeding. One way of treating these people is to administer exogenous FVIII. However, the immune system of some patients consider the exogenous FVIII as foreign and develop anti-FVIII antibodies. These antibodies inhibit the procoagulant activity of FVIII and hence are also known as FVIII inhibitors. Sébastien in 1999 showed that these antibodies possess catalytic activity and Bharath later on from 2004-2009 studied the mechanisms by which these antibodies inactivate FVIII. The enzymatic activities were studied by incubating the patient's IgG with FVIII. The resultant mixture was analyzed using SDS-PAGE gels for the hydrolysis of FVIII. They have used intravenous immunoglobulin, a pool of IgG from 1000's of healthy blood donors as a control along with the molecules incubated alone in the buffer to check for auto-degradation of proteins. Due to my limited knowledge of enzyme kinetics, I would suggest the readers to refer the publications listed below for more information.

Suggested Reading:
1. Lacroix-Desmazes S, Moreau A, Sooryanarayana, Bonnemain C, Stieltjes N, Pashov A, Sultan Y, Hoebeke J, Kazatchkine MD, Kaveri SV. Catalytic activity of antibodies against factor VIII in patients with hemophilia A. Nat Med. 1999 Sep;5(9):1044-7.
2. Lacroix-Desmazes S, Wootla B, Dasgupta S, Delignat S, Bayry J, Reinbolt J, Hoebeke J, Saenko E, Kazatchkine MD, Friboulet A, Christophe O, Nagaraja V, Kaveri SV. Catalytic IgG from patients with hemophilia A inactivate therapeutic factor VIII. J Immunol. 2006 Jul 15;177(2):1355-63.
3. Wootla B, Mahendra A, Dimitrov JD, Friboulet A, Borel-Derlon A, Rao DN, Uda T, Borg JY, Bayry J, Kaveri SV, Lacroix-Desmazes S. Factor VIII-hydrolyzing IgG in acquired and congenital hemophilia. FEBS Lett. 2009 Aug 6;583(15):2565-72.